1. Field of the Invention
The present invention relates to a diagnostic method and apparatus for the detection of cancer in a living patient.
2. Prior Art
Attempts utilizing the technique of nuclear magnetic resonance (NMR) to aid in arriving at a clinical diagnosis of cancer are well known in the prior art.
Damadian was the first to propose any medical use for nuclear magnetic resonance (NMR) and that was for the detection of malignancy in tissue. See R. Damadian, "Tumor Detection by Nuclear Magnetic Resonance," Science 171:1151-1153 (1971). U.S. Pat. No. 3,789,832 issued to Damadian covers an apparatus and method for application of nuclear magnetic resonance to surgically removed specimens to measure T.sub.1 and T.sub.2 for proton relaxation times, which values, compared against values for healthy tissue, were taken as an indication of cancer. U.S. Pat. Nos. 4,411,270 and 4,354,499 issued to Damadian cover apparatus and method for cancer detection with NMR imaging and scanning of whole-body specimens.
A number of other investigators also reported that nuclear magnetic resonance relaxation times (T.sub.1) for water protons in organs of tumor-bearing animals have higher values than the corresponding T.sub.1 for water structure in organs of healthy animals. See Frey et al, J. Natl. Cancer Inst. 49,903 (1972); Inch et al, J. Natl. Cancer Inst. 52,353 (1974); Iijima et al, Physiol. Chem, and Physics 5, 431 (1973) ; and Hazlewood et al, J. Natl. Cancer Inst. 52, 1849 (1974).
Today, despite uncertainty regarding mechanistic details, it is well known that biophysical changes which occur in malignant cells often result in alterations of the proton NMR signal. See D. G. Taylor et al, "A Review of the Magnetic Resonance Response of Biological Tissue and Its Applicability to the Diagnosis of Cancer by NMR Radiology," Computed Tomography, 5:122-133 (1981). Such changes form the physical basis for detection of tumors by proton NMR imaging. See R. Zimmerman et al, "Cerebral NMR: Diagnostic Evaluation of Brain Tumors by Partial Saturation Technique with Resistive NMR," Neuroradiology 27:9-15 (1985) and K. Ohtomo, "Hepatic Tumors: Differentiation by Transverse Relaxation Time (T.sub.2) of Magnetic Resonance Imaging," Radiology 155:421-423 (1985). However, NMR imaging is not likely to be widely applied as a screening test for malignancy because of accessibility and economic factors.
Proton NMR studies on excised tumors, as well as on plasma and serum, from experimental animals and patients have often shown differences in the relaxation parameters T.sub.1, T.sub.2 and T.sub.2 *, T.sub.2 * being a combination of T.sub.2 from intrinsic relaxation and relaxation induced by magnetic field inhomogeneities, as a function of malignancy. Such findings have been reported by the following:
L. McLachlan, "Cancer-induced Decreases in Human Plasma Proton NMR Relaxation Rates," Phys. Med. Biol. 25:309-315 (1980); PA0 F. Smith et al, "Nuclear Magnetic Resonance Imaging of the Pancreas," Radiology 142:677-680 (1982); PA0 P. Beall et al, "The Systemic Effect of Elevated Tissue and Serum Relaxation Times for Water in Animals and Humans with Cancers," NMR Basic Principles and Progress, P. Diehl et al, Eds., 19:39-57 (1981); PA0 R. Floyd, "Time Course of Tissue Water Proton Spin-lattice Relaxation in Mice Developing Ascites Tumor," Cancer Res. 34:89-91 (1974); PA0 C. Hazlewood et al, "Relationship Between Hydration and Proton Nuclear Magnetic Resonance Relaxation Times in Tissues of Tumor Bearing and Nontumor Bearing Mice: Implications for Cancer Detection," J. Natl. Cancer Inst. 52:1849-1853 (1974); and PA0 R. Klimek et al, "A Discussion of Nuclear Magnetic Resonance (NMR) Relaxation Time of Tumors in Terms of Their Interpretation as Self-organizing Dissipative Structures, and of Their Study of NMR Zeugmatographic Imaging," Ginekol Pol. 52:493-502 (1981).
However, due to extensive overlap of groups and small differences between the means of groups, these methodologies are not clinically useful.
While most of the prior art mentioned above describes applications of NMR to analysis of tissue, it is also known to subject bodily fluids to such analysis. This is described, for example, by Beall et al., supra.
The foregoing prior art studies and methods, as well as all other prior art NMR methods for the detection of malignancy, rely on the observation of the composite NMR signal arising from all protons in the tissue or blood derived samples. This composite signal is dominated by the protons of water, obscuring the NMR signal from other proton-containing constituents of the sample. Indeed, the prior art believed that the apparent correlation between malignancy and observed changes in NMR parameters was due to "changes in water structure," quoting Frey et al., supra.
In other applications of proton NMR spectroscopy, it was known to suppress the signal from the solvent (such as water), in a sample.
It was discovered that the components of the NMR spectrum which have significant predictive value may be masked by other materials in the sample. By eliminating the masking, as by eliminating the water signal, the previously masked spectrum of these components was revealed. In co-pending application "Process for the Detection of Cancer Using Nuclear Magnetic Resonance," U.S. Ser. No. 833,840, filed February 26, 1986, the teachings of which are incorporated herein by reference, those discoveries were incorporated into a reliable method of diagnosing the presence of cancer in a living patient.
In accordance with that invention, a sample of a patient's bodily fluid is subjected to nuclear magnetic resonance spectroscopy to generate a nuclear magnetic resonance spectrum. A resonance line generated by a non-water component of the sample is selected, and the full width of this resonance line, e.g., at half its height, is measured. The full width so measured has proved to be a statistically reliable measure of the presence or absence of cancer in the patient.
The above described test of water-suppressed proton NMR of plasma discriminates between persons with untreated cancers and others with better than 90% accuracy. As such, the test was widely acclaimed as one of the most important inventions of the decade. No prior non-invasive test for cancer had reached even close to that level of accuracy. False positive results, however, have been obtained. In accordance with the present invention, It has been discerned that the major source of false positive results are those persons with high levels of plasma triglycerides.
Consequently, with the discovery of the present invention, a method and apparatus was developed to improve upon the accuracy of a non-invasive method to determine the presence of cancer in a living patient.
These and other objects and features of the present invention will become apparent to those skilled in the art from a reading of the description of the invention, taken together with the drawing, which follow.